Human leukocyte antigen (HLA)-matched allogeneic hematopoietic transplantation has revolutionized the treatment of leukemia, lymphoma, and inherited hematopoietic stem cell diseases (Stockerl-Golstein et al., 1999). Donor T cells contained in the allograft are vital for promoting engraftment, eradicating malignant cells [the graft-versus-leukemia (GVL) effect], and reconstituting immunity. Unfortunately, these cells are known to mediate Graft-versus-host disease (“GVHD”), which is an attack on recipient tissues. GVHD and the global immunosuppression needed to prevent or treat it underlie the major reasons for transplant failures: infection and neoplastic relapse. Furthermore, only 60% of patients have matched sibling or unrelated donors, and even fewer make it to transplant because of the delays due to the donor search and bone marrow harvesting (Martelli et al., 2002). However, virtually every patient has a family member who is identical for one HLA haplotype and fully mismatched for the other, and thus could immediately serve as a donor.
Transplantation across the histocompatibility barrier has been made possible by extensive T cell depletion of the graft to help prevent GVHD, and transplantation of large numbers of hematopoietic stem cells to help overcome rejection (Martelli et al., 2002; Aversa et al., 1994, 1998; Bachar-Lustig et al, 1995; Reisner & Martelli, 1999; U.S. Pat. No. 5,806,529). Depletion of T cells, however, significantly reduces engraftment success and eliminates the GVL effect.
Alternative strategies have been proposed such as treating the subjects undergoing bone marrow transplantation with immunosuppressive regimens, to avoid GVHD. However, such immunosuppressive treatments are not specific and cause a general and negative immunosuppression in patients.
Patent application US20020127208 discloses a method of transplanting hematopoietic cells from an allogeneic donor comprising the administration of mononuclear cells, including NK cells, which are treated so as to substantially reduce their ability to cause GVHD while they retain their ability to proliferate in the recipient. More particularly, the cells are treated with a chemotherapeutic agent which decreases the biological activity of the mononuclear cells. Similarly, U.S. Pat. No. 5,800,539 discloses a method of transplanting hematopoietic cells from an allogeneic donor comprising the administration of mononuclear cells which are treated so as to render them incapable of proliferating and causing a GVHD. These two documents thus disclose pre-treatment of the graft to reduce the activity of mononuclear cells, suggesting that these cells, including the Natural Killer (“NK”) cells have the ability to cause GVHD.